Mounting evidence for the use of hyperthermia (HT) with radiation (RT) and chemotherapy continues to build. Phase III trials show an improve response rate, local control, and survival of a number of tumor sites and histologies. Hyperthermia still awaits widespread acceptance, in large put due to the technical challenges of heating tumors and imprecise knowledge of thermal dosimetry. Successful deployment of three dimensional non-invasive thermometry is paramount to the widespread application of HT in the broader community. This project encompasses four specific aims. First, we propose to conduct a phase II trial testing the feasibility and accuracy of non-invasive thermometry with pre-treatment planning and thermal modeling will ultimately allow for real time three-dimensional control of temperatures during HT. We will also continue our phase II trial of clinical outcome in superficial malignancies as related to thermal dose prescription and the modeling studies of pre-treatment planning optimization for deep seated tumors. The second aim establishes cooperation with other institution in phase III trials for high risk sarcoma (EORTC 62961/ESHO RHT-95) and locally advanced rectal cancer. Carefully designed and executed phase III trials exploring hyperthermia in combination with chemotherapy and radiotherapy in patients with potentially curable malignancies are critical for establishing hyperthermia as a significant treatment modality. The third aim explores novel approaches to tumor drug delivery utilizing hyperthermia, intra-peritoneal drug administration, and liposomally encapsulated doxorubicin for ovarian and breast carcinoma. These protocols are a direct translation of our compelling preclinical data, and establish a new paradigm for hyperthermia as a modality which specifically augments locoregional delivery of systemic chemotherapy. The fourth aim of the project has been the study of interactions of HT with tumor physiology. We published the first clinical data indicating that the presence of hypoxia is a negative prognostic factor for overall survival of patients with large high grade soft tissue sarcomas (the main failure pattern was metastases). In a series that parallels our original sarcoma series, we will now explore human sarcoma tumor physiology with the addition of chemotherapy as well as HT and RT. Similar studies are planned for locally advanced breast cancer using neoadjuvant liposomal doxorubicin and HT.